Optimising ART sub-Saharan Africa Presented by Prof R.P.H. Peters Prof Venter is acknowledged for provision of some of the slides Pretoria, Saturday 17th February 2018

Outline of talk Outline of talk Optimising ART in sub-Saharan Africa HIV epidemic and scale of the ART programme Positive and negative effects of ART How to provide life long ART Optimising first-line ART Optimising second-line ART Conclusion HIV epidemic and scale of the ART programme Positive and negative effects of ART How to provide life long ART Optimising first-line ART Optimising second-line ART Conclusion

HIV epidemic in sub-Saharan Africa

HIV epidemic in South Africa HIV and South Africa HIV epidemic in South Africa UNAIDS country progress report

ART programme evolution HIV and South Africa ART programme evolution 2004 2010 2016 2013 ART in public sector CD4 count <200 cells/mm3 CD4 count <350 cells/mm CD4 count <500 cells/mm CD4 count any cells/mm Pregnant women WHO stages & specific conditions

Importance of ART: for population (1) Early (At diagnosis, but 350-550 cells/mm3 as inclusion) vs. Delayed (CD4 <250 cells/mm3 or AIDS-related symptoms) Cohen MS et al. NEJM 2011

HR = 0.37 or 96.3% reduction in transmission Importance of ART: for population (2) N=27 HR = 0.37 or 96.3% reduction in transmission % N=1 Delayed Immediate

Importance of ART: for population (3) Approach to HIV epidemic control

Importance of ART: for individual ART initiation CD4 >500 cells/mm3 vs. CD4 <350 cells/mm3 Clinical trial START Study Group. NEJM 2013

Impact of ART programme Reduction in mortality and morbidity Prolonged lifespan Reduction in (opportunistic) infections Bor J et al. Science 2013 Hoogendoorn JC et al. Epidemiol Infect 2017

ART “normalizes” life-expectancy Life-expectancy catching-up with HIV-negative individuals if on ART and virologically suppressed

Morbidity associated with ART But how about long-term side-effects and accelerated ageing associated with lifelong ART? ATHENA cohort

Morbidity and HIV in Zimbabwe Hypertension CKD Cancer Depression Malignancy Smit M et al. AIDS 2018

Morbidity associated with ART Effects of (chronic) HIV and ART on the eye? Conjunctival ‘sludging’ Anterior segment conditions Accelerated ageing (cataract) Poster segment conditions (HIV retinopathy) Conjunctival sludging Cataract Cotton-Wool spots Schaftenaar E et al. Epidemiol Infect 2017

How to provide lifelong ART? Current cost ART in RSA: R 6 billion / annum

A quick recap… HIV life cycle Current cost ART in RSA: R 6 billion / annum

Smits RL et al. Frontiers Genetics 2013 Current cost ART in RSA: R 6 billion / annum

How do we ensure lifelong ART with good treatment outcomes for 7 million people in South Africa? Effective drugs: rapid and strong suppression

How do we ensure lifelong ART with good treatment outcomes for 7 million people in South Africa? Effective drugs: rapid and strong suppression Kanters S et al. Lancet HIV 2016

How do we ensure lifelong ART with good treatment outcomes for 7 million people in South Africa? Effective drugs: rapid and strong suppression Kanters S et al. Lancet HIV 2016

How do we ensure lifelong ART with good treatment outcomes for 7 million people in South Africa? 2) Well-tolerated drugs: limited side-effects Kanters S et al. Lancet HIV 2016

How do we ensure lifelong ART with good treatment outcomes for 7 million people in South Africa? Affordable drugs: cost of components, fixed dose combinations and adherence/resistance barrier of 1st-line drugs *For example - if daily ART are would be R1 cheaper: -This would save R30 per month -This would save R 365 per patient per year -This would save the programme (4 million people on ART) a total of R 1 460 000 per annum (24%)

WHO Guidelines 1st line regimen

ART regimens in South Africa

Side effect (and size) driver, resistance weak link First-line ART regimen in South Africa TDF XTC EFV Side effect (and size) driver, resistance weak link Cost driver

Side effect (and size) driver, resistance weak link First-line ART regimen in South Africa TDF XTC EFV Side effect (and size) driver, resistance weak link Cost driver

High value of tenofovir 1st line recommendation by WHO Well tolerated, daily Hep B treatment for free Renal, bone concerns Replacing TDF for TAF -Reduction in cost (300mg vs. 25mg) -Same benefits but less side-effects

Side effect (and size) driver, resistance weak link First-line ART regimen in South Africa TDF XTC EFV Side effect (and size) driver, resistance weak link Cost driver

Pros and cons of efavirenz Daily, cheap, co-formulated, huge experience base, TB (and most everything else)-friendly EFV side effects predictable, treatable, substitutions relatively easy Limited genetic resistance barrier Increasing recognition of CNS side effects Rash, hepatitis, gynaecomastia, lipids Depression and serious and fatal rare CNS side effects recently recognised

Depression Efavirenz (6%) 2x higher risk for suicidality Meta-analysis n=5332, 4 RCT Efavirenz (6%) 2x higher risk for suicidality Rilpivirine (8%) Elvitegravir/COBI (5%) Raltegravir (6%) Atazanavir/r (2%) For composite endpoint ‘Only’ trend for completed/attempted suicide (17 events occured) EFV EFV-free Lack of association between use of efavirenz and death from suicide: evidence from the D:A:D study #O315 Wednesday 5 November C. Smith; L. Ryom; A. d’Arminio Monforte; P. Reiss; A. Mocroft; W. El-Sadr; R. Weber; M. Law; C. Sabin; J. Lundgren. Cohen et al., Lancet 2011; Molina et al, Lancet 2011; Elion et al., JAIDS 2013; Mollan et al, Ann Intern Med, 2014

TDF XTC EFV First-line ART regimen in South Africa Efavirenz 400mg? Dolutegravir? Rilpivirine: TB, VL and food issues

Efavirenz 400mg.. Non-inferior to EFV 600mg but less side-effects Studies currently underway – pregnancy and TB Then, if mass switch to 400mg; cost saving ≈ 5-10%

Efavirenz 400mg.. Encore1 Study Group. Lancet Infect Dis 2015

Efavirenz 400mg.. Encore1 Study Group. Lancet Infect Dis 2015

Efavirenz 400mg.. “In countries with pre-treatment HIVDR to NNRTIs below 10%, and no availability of low-cost generic DTG in a fixed-dose combination, transition from EFV600 to EFV400 might have some financial advantages. However, this would introduce the potential for 2 transition events (from EFV600 to EFV400, then from EFV400 to DTG-based regimens). Countries with pre-treatment HIVDR to NNRTIs at or above 10% should avoid the use of EFV400-containing regimens, and move to DTG as the preferred first-line regimen” TASP trial: 9% pre-treatment drug resistance; largely NNRTIs

Efavirenz 400mg.. “In countries with pre-treatment HIVDR to NNRTIs below 10%, and no availability of low-cost generic DTG in a fixed-dose combination, transition from EFV600 to EFV400 might have some financial advantages. However, this would introduce the potential for 2 transition events (from EFV600 to EFV400, then from EFV400 to DTG-based regimens). Countries with pre-treatment HIVDR to NNRTIs at or above 10% should avoid the use of EFV400-containing regimens, and move to DTG as the preferred first-line regimen” Pre-therapy drug-resistance in the Cape Winelands Van Zyl GU et al. AIDS 2017

Dolutegravir Strong drug (high resistance barrier) with very good efficacy 50mg once-daily Very good efficacy Potential to be low cost and co-formulated: raltegravir and elvitegravir expensive Increases metformin and reduces rifampicin levels Minimal toxicity – but NEW data re CNS and IRIS..

Dolutegravir

The US and EU has long moved on from EFV-based treatment Dolutegravir Major parameters EFV 600 DTG Occurrence of SAEs comparable Better virologic suppression  Better CD4 recovery Less treatment discontinuation Less occurrence of subjective side effects Lower potential for drug–drug interactions Efficacy in HIV-2 infection Efficacy in TB coinfection Efficacy and safety in pregnant/breastfeeding women Availability as generic formulations The US and EU has long moved on from EFV-based treatment

Summary of options for 1st line Major outcomes INSTI vs. EFV600 DTG vs. other INSTI DTG vs. EFV600 DTG vs. EFV400 EFV400 vs. EFV600 Quality of evidence Viral suppression INSTI better DTG better comparable* comparable moderate CD4 recovery INSTI better EFV400 better Treatment discontinuation Mortality low AIDS progression SAE *Estimated effects favored DTG, but statistical analysis not significant WHO Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection – What’s New Policy Brief, November 2015. Available at http://www.who.int/hiv/pub/arv/policy-brief-arv-2015/en/

New combination: TAF/FTC/DTG Almost unbreakable – 600 000 people on first-line DTG, no resistance DTG slightly cheaper than EFV, TAF much cheaper than TDF – generics: immediate 20% price reduction (CHAI: closer to 50%) Possibility of harmony for >12 years (and possibly below) WDF Venter et al. Curr Opinion HIV AIDS 2017

Optimisation of PIs: side-effect issues

Optimisation of PIs: safety issues Use of PI in a different way Non-inferiority study of DRV/r at lower dose vs. LPV/r  Reduced pill burden Better toxicity profile Higher resistance profile Prodrugs and new formulations of current PIs

Summary and conclusion (1) ART programme in South Africa has evolved hugely Benefit for the individual Benefit for the population Large population ageing on ART and ‘at risk’ for morbidity and resistance Treatment optimisation important Tolerability and treatment outcomes Cost and affordability

Summary and conclusion (2) First-line regimen likely to change in public sectors across sub-Saharan Africa in the coming years EFV400mg, DTG and TAF valuable options

Thank you! Acknowledgements Unitaid Southern African HIV Clinicians Society Prof Francois Venter